The long term goal of this research project is to elucidate the basis for the actions of the cannabinoids (CBs) at the molecular level. To this end, we are developing the elements of an understanding of the relationships between cannabinoid ligand structure; cannabinoid receptor structure; and cannabinoid receptor activation at an atomic level of detail. The research plan includes two emphases: ligand-receptor recognition and ligand-induced receptor activation/inactivation and is based upon 3D computer models of the CB1 and CB2 receptors that we have developed and refined during the current grant period. Our recent microsecond timescale molecular dynamics simulations of the CB2 receptor in a POPC bilayer have yielded important insights concerning the differences between CB1 and CB2. We will use this information here to explore the interactions important for the maintenance of the CB2 receptor inactive state and those responsible for the generation of the CB2 activated state. A binding site model for CB2 inverse agonists/antagonists will be developed in order to identify those interactions necessary for the production of inverse agonism at CB2. Studies will also be undertaken to identify the interaction site(s) for novel CB1 allosteric modulators with the goal of designing more potent modulators. At each step, our work will be aided and supplemented by collaboration with experimental medicinal chemists, molecular biologists and pharmacologists. Collaborative studies will be used to test our models in an iterative fashion with the goal that these models represent the current state of knowledge in the cannabinoid field. The information about cannabinoid receptor structure and binding modes of ligands that will emerge from the collaborative studies proposed here will aid in fundamental structure-function studies of this important class of receptors and will also aid in the design of improved therapeutic agents based on the cannabinoids.